Transmission of HIV-1, development of persistent infection, and establishment of the prognostically-important plasma viral load setpoint, are the three critical events that sustain the HIV-1 pandemic and lead to the clinical sequelae of AIDS. A vaccine that favorably impacts any one of these key events could have a major impact on the HIV/AIDS pandemic; a practically achievable vaccine in the near term might impact all three, whereas an ideal vaccine would induce sterilizing immunity. Thus, we would propose that rational HIV-1 vaccine development requires an in-depth understanding of viral and host determinants of HIV-1 transmission, persistence, and partial containment in primary human infection. This should reveal critical viral vulnerabilities as well as host immune defense mechanisms amenable to vaccine-elicited augmentation. The Principal Investigator has thus developed a research plan that targets four essential aspects of viral-host interaction in acute and early infection in order to test the following overall hypothesis: HIV-1 leads to chronic persistent infection rather than acutely lethal disease because elements of the adaptive immune system partially constrain viral replication beginning in the earliest stages of primary infection. The goal of this project is not only to test rigorously this overarching hypothesis, but then to dissect and elucidate those viral and host factors that mediate this effect. Aim 1. To elucidate the genetic, biologic, antigenic, and structural characteristics of sexually transmitted virus and mechanisms underlying virus transmission. Aim 2. To elucidate the ontogeny of HIV-1 specific T cell, natural killer (NK) cell, and dendritic cell (DC) responses in acute and early HIV-1 Infection. Aim 3. To elucidate the ontogeny of HIV-1 specific B cell responses in acute and early HIV-1 infection. Aim 4. To elucidate host genetic differences affecting susceptibility to HIV-1 infection and disease progression in acute and early HIV-1 infection. Thus, each R01 aim addresses important scientific gaps in our understanding of early viral, immunologic, and host genetic influences on primary HIV-1 infection, thus providing critical information to drive HIV-1 vaccine development.